The Mitogen-Activated Protein Kinase (MAPK) network consists of tightly interconnected signalling pathways involved in diverse cellular processes, such as cell cycle, survival, apoptosis and differentiation. Although several studies reported the involvement of these signalling cascades in cancer deregulations, the precise mechanisms underlying their influence on the balance between cell proliferation and cell death (cell fate decision) in pathological circumstances remain elusive. Based on an extensive analysis of published data, we have built a comprehensive and generic reaction map for the MAPK signalling network, using CellDesigner software. In order to explore the MAPK responses to different stimuli and better understand their contributions to cell fate decision, we have considered the most crucial components and interactions and encoded them into a logical model, using the software GINsim. Our logical model analysis particularly focuses on urinary bladder cancer, where MAPK network deregulations have often been associated with specific phenotypes. To cope with the combinatorial explosion of the number of states, we have applied novel algorithms for model reduction and for the compression of state transition graphs, both implemented into the software GINsim. The results of systematic simulations for different signal combinations and network perturbations were found globally coherent with published data. In silico experiments further enabled us to delineate the roles of specific components, cross-talks and regulatory feedbacks in cell fate decision. Finally, tentative proliferative or anti-proliferative mechanisms can be connected with established bladder cancer deregulations, namely Epidermal Growth Factor Receptor (EGFR) over-expression and Fibroblast Growth Factor Receptor 3 (FGFR3) activating mutations.

We have identified a novel pathway that links SIRT1 down-regulation to hypoxia-induced EMT in lung cancer cells and may shed light on the development of novel antitumor therapeutics.

We have followed Sp1 expression in primary human T lymphocytes induced, via CD2 plus CD28 costimulation, to sustained proliferation and subsequent return to quiescence. Binding of Sp1 to wheat germ agglutinin lectin was not modified following activation, indicating that the overall glycosylation of the protein was unchanged. Sp1 underwent, instead, a major dephosphorylation that correlated with cyclin A expression and, thus, with cell cycle progression. A similar change was observed in T cells that re-entered cell cycle following secondary interleukin-2 stimulation, as well as in serum-induced proliferating NIH/3T3 fibroblasts. Phosphatase 2A (PP2A) appears involved because 1) treatment of dividing cells with okadaic acid or cantharidin inhibited Sp1 dephosphorylation and 2) PP2A dephosphorylated Sp1 in vitro and strongly interacted with Sp1 in vivo. Sp1 dephosphorylation is likely to increase its transcriptional activity because PP2A overexpression potentiated Sp1 site-driven chloramphenicol acetyltransferase expression in dividing Kit225 T cells and okadaic acid reversed this effect. This increase might be mediated by a stronger affinity of dephosphorylated Sp1 for DNA, as illustrated by the reduced DNA occupancy by hyperphosphorylated Sp factors from cantharidin-or nocodazole-treated cells. Finally, Sp1 dephosphorylation appears to occur throughout cell cycle except for mitosis, a likely common feature to all cycling cells.Sp1 is the founding member of a multigene family of transcription factors including Sp1, Sp2, Sp3, Sp4 (see Refs. 1-3 for reviews), and Sp5 proteins (4, 5). Both Sp1 and Sp3 are abundant and ubiquitous, whereas Sp4 is mainly expressed in neuronal tissues and Sp5 exhibits a dynamic and highly restricted expression pattern during embryogenesis. This protein family shares three highly conserved zinc finger DNA binding motifs that recognize GC or GT/CACC boxes present in many promoters. Sp1 was first viewed as a constitutive transcriptional activator regulating basal expression of many cellular and viral genes. However, it is now established that Sp1 activity is modulated in response to numerous signals and that this factor plays a critical role in cell growth and differentiation. Sp1 mediates the induction of dihydrofolate reductase (6) and thymidine kinase (7) genes associated with DNA synthesis and is therefore intricately linked to growth/cell cycle progression. In line with this, the ectopic expression of truncated Sp1 prolongs the S phase and reduces the growth rate (8). Conversely, Sp1 mediates cell division arrest by up-regulating the expression of genes coding for negative regulators of the cell cycle such as p2lWaf1/Cip1 , in p53-dependent growth control (9) or p53-independent pathway of terminal differentiation (10 -12).Sp1's manifold roles can be reconciled if one integrates the multiple time-ordered regulations to which this factor is itself submitted. First, Sp1 is a direct target of numerous cell cycle regulators, which activate or repress its activity. For instance, cyclin A (13...

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